Cell-specific actions of interleukin (IL)-1 in the pressure-overloaded myocardium
Final Report Abstract
The aim of my project was to investigate how the activation of IL-1-dependent inflammatory pathways in different cardiac cell types may regulate remodeling in pressure-overloaded hearts. Due to the Covid-19 pandemic-related restrictions, but also because of the fact that the Professor Frangogiannis’ laboratory has recently obtained very interesting preliminary data on the roles of pericytes and fibroblasts in cardiac pathophysiology, especially diabetic cardiomyopathy, the initial topic of my research work has been modified to study the involvement of different pathways in fibroblasts and pericytes in various models of cardiac pathology. Since transforming growth factor (TGF)b, acting through its receptor TbR2, is a critical mediator in the processes of inflammation, angiogenesis and fibrosis, the aim of my first project was to examine the fibroblasts-specific TbR2-mediated actions in diabetic hearts. To study this, I generated a mouse model with a fibroblast-specific TbR2 knockout (FTbR2KO) using the cre-loxP system. These mice were bred to diabetic and lean backgrounds and sacrificed at 6 months of age. The deletion of TbR2 in fibroblasts in diabetes resulted in the improvement of cardiac function and the reductions in collagen volume, thickness of collagen fibers and cardiomyocyte size compared to corresponding diabetic controls. Currently, RNA sequencing analyses are in progress to identify potential factors underlying paracrine actions of fibroblasts on cardiomyocytes and to detect other important pathways differentially expressed across the groups studied. Encouraged by these findings, we wanted to investigate how the fibroblast-specific knockout of TbR2 may influence reparative and remodeling processes following myocardial infarction (MI). The results showed that the deletion of TbR2 in fibroblasts did not have any relevant influence on cardiac function or the infarct scar size in mice which survived, however it caused a significantly higher mortality and changes in the scar composition. At present, further experiments, including RNA sequencing are ongoing to understand better the pathomechanisms underlying the above-mentioned findings. The aim of my next project was to investigate the role of pericytes and pericyte-derived cells in a pressure-overloaded myocardium using a transverse aortic constriction (TAC) model. The data obtained so far showed that the pericyte-derived population of cells resembles transcriptomically much more fibroblasts than pericytes and thus may have a significant influence on the TAC-induced fibrosis. To examine if TbR2 or integrin β1, which both may modulate pericyte functions, determine pericyte and pericyte-derived cell actions in pressure-overloaded myocardium, I generated mice with the pericyte-specific TbR2 or integrin B1 loss which were subjected to TAC. Currently, the data from these models are analyzed.
